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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impressive inhibition of tumor growth has been observed after transduction of cytokine genes into tumor cells. Secreted cytokines do not affect the proliferation of a tumor directly but activate a host immune reaction strong enough to overcome its oncogenic capacity. However, the reaction mechanisms activated are difficult to interpret; because these mechanisms have been derived from experiments with different tumors, comparisons are hindered. To compare the reactive mechanisms induced by each cytokine, BALB/c mice were challenged with the parental cells of the syngeneic spontaneous mammary adenocarcinoma TSA, or with TSA cells engineered to release IL2, IL4, IL7, IL10, IFN alpha, IFN gamma, and TNF alpha, and the tumor growth area was studied histologically, ultrastructurally, and immunohistochemically. These observations were integrated with data on the growth and rejection patterns of TSA cells in mice depleted of natural killer (NK) cells, granulocytes, CD4+, or CD8+ lymphocytes. The rejection of TSA-IL2 and TSA-TNF alpha cells was associated with the massive presence of neutrophils, that of TSA-IL4 and TSA-IL7 cells with neutrophils and very small areas of colliquative necrosis, and that of TSA-IFN alpha and TSA-IL10 cells with extensive areas of ischemic-coagulative necrosis and some neutrophils. TSA-IFN gamma cells displayed a delay in growth, but were not rejected. Their growth areas comprised necrotic zones of ischemic necrosis devoid of neutrophils. The selective depletion experiments demonstrated that rejection of engineered TSA cells depends on several leukocyte populations. The weight of each population varied with the secreted cytokine, although neutrophils and CD8+ lymphocytes constantly played the major role. Employment of the same tumor line engineered with the genes of different cytokines showed that each cytokine evokes a distinct reaction and that tumor inhibition results from a complex mechanism in which neutrophils and CD8+ lymphocytes and ischemic necrosis are of primary importance.
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PMID:Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-alpha, IFN-gamma, and TNF-alpha. 856 77

The antitumor activity of recombinant murine interleukin-12 (rIL-12) is documented by a large set of data from numerous mouse models. Because the cellular and molecular mechanisms by which rIL-12 impairs tumor growth are still not fully defined, we compared the effects of local and systemic rIL-12 administration in mice harboring an invasive 7-day-old moderately differentiated and spontaneously metastasizing mammary adenocarcinoma (TSA). Whereas the immune events elicited via the two routes of rIL-12 administration seem to be the same, systemic rIL-12 is markedly more effective; tumor destruction is dependent on a prompt antitumor response resulting from the cooperation of several subsets of reactive cells. The reactions that seem to play a key role are: (a) indirect inhibition of angiogenesis by secondary cytokines (mainly IFN-gamma) and third-level chemokines (inducible protein 10 and monokine induced by IFN-gamma); (b) systemic activation of leukocyte subsets capable of producing proinflammatory cytokines, CTLs, and antitumor antibodies; and (c) destruction of tumor vessels by polymorphonuclear cells. The markedly higher efficacy of systemic rIL-12 seems to rest on its ability to recruit these systemic reactions more quickly and efficiently than local rIL-12.
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PMID:Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12. 992 56

The CC chemokine ligand (CCL)16 exerts chemotactic activity on human monocytes and lymphocytes. Although no murine homologous has been defined, the TSA mouse adenocarcinoma cells engineered to express human CCL16 are rapidly rejected by syngenic mice. An adenovirus encoding CCL16 (AdCCL16) was generated using a Cre-Lox-based system and was used to determine whether this chemokine might also block pre-existing tumors. Both recombinant and viral CCL16 showed in vitro chemotactic activity for murine CD4(+) and CD8(+) lymphocytes and dendritic cells (DC). AdCCL16, but not the control empty vector, when injected in established nodules significantly delayed tumor growth. Immunohistochemistry revealed accumulation of CD4(+) and CD8(+) T cells and DC in the treated tumors as well as in draining lymph nodes. DC from such lymph nodes stimulated IFN-gamma by a T cell clone specific for the known TSA tumor-associated Ag (TAA), suggesting the tumor origin of these cells. Lymphocytes from the same nodes showed specific CTL activity against TSA tumor cells and their immunodominant TAA peptide. Antitumor activity required CD4, CD8, and IFN-gamma production, as shown using subset-depleted and knockout mice. Despite the robust and rapid immune response triggered by intratumoral injection of AdCCL16, the lesions were not completely rejected; however, the same treatment given before surgical excision of primary lesions prevented metastatic spread and cured 63% of mice bearing the 4T1 mammary adenocarcinoma, which is perhaps the most compelling model of spontaneous metastasis.
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PMID:Intralesional injection of adenovirus encoding CC chemokine ligand 16 inhibits mammary tumor growth and prevents metastatic-induced death after surgical removal of the treated primary tumor. 1503 14

We have developed new, simple, and efficient procedures for the synthesis of two promising histone deacetylase inhibitors (HDIs), CI-994, (N-(2-aminophenyl)-4-acetylaminobenzamide), and MS-275 (N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide) from commercially available acetamidobenzoic acid and 3-(hydroxymethyl)pyridine, respectively. The procedures provide CI-994 and MS-275 in 80% and 72% overall yields, respectively. We found that the combination of four HDIs (CI-994, MS-275, SAHA, and TSA) with retinoids all-trans-retinoic acid (ATRA) or 13-cis-retinoic acid (13-CRA) or our atypical retinoic acid metabolism blocking agents (RAMBAs) 1 (VN/14-1) or 2 (VN/66-1) produced synergistic anti-neoplastic activity on human LNCaP prostate cancer cells. The combination of 2 and SAHA induced G1 and G2/M cell cycle arrest and a decrease in the S phase in LNCaP cells. 2+SAHA treatment effectively down-regulated cyclin D1 and cdk4, and up-regulated pro-differentiation markers cytokeratins 8/18 and pro-apoptotic Bad and Bax. Following subcutaneous administration, 2, SAHA or 2+SAHA were well tolerated and caused significant suppression/regression of tumor growth compared with control. These results demonstrate that compound 2 and its combination with SAHA are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.
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PMID:Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts. 1816 65

Histone deacetylase (HDAC) inhibitors potently inhibit tumor growth and are currently being evaluated for their efficacy as chemosensitizers and radiosensitizers. This efficacy is likely to be limited by the fact that HDAC inhibitors also induce cell cycle arrest. Deletion of the class I HDAC Rpd3 has been shown to specifically suppress the sensitivity of Saccharomyces cerevisiae DNA damage checkpoint mutants to UV and hydroxyurea. We show that in the fission yeast Schizosaccharomyces pombe, inhibition of the homologous class I HDAC specifically suppresses the DNA damage sensitivity of checkpoint mutants. Importantly, the prototype HDAC inhibitor Trichostatin A also suppressed the sensitivity of DNA damage checkpoint but not of DNA repair mutants to UV and HU. TSA suppressed DNA damage activity independently of the mitogen-activated protein kinase-dependent and spindle checkpoint pathways. We show that TSA delays progression into mitosis and propose that this is the main mechanism for suppression of the DNA damage sensitivity of S. pombe checkpoint mutants, partially compensating for the loss of the G(2) checkpoint pathway. Our studies also show that the ability of HDAC inhibitors to suppress DNA damage sensitivity is not species specific. Class I HDACs are the major target of HDAC inhibitors and cancer cells are often defective in checkpoint activation. Effective use of these agents as chemosensitizers and radiosensitizers may require specific treatment schedules that circumvent their inhibition of cell cycle progression.
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PMID:Inhibition of type I histone deacetylase increases resistance of checkpoint-deficient cells to genotoxic agents through mitotic delay. 1972 88

Monoclonal antibodies developed against immunogenic proteins (Tumor Specific Antigens/TSA's) that are expressed in human cancers, display a unique behavioral pattern. They appear to serve in a dual role. This includes the early recognition of these immunogenic membrane proteins that can serve as diagnostic markers, and the targeting of such markers for the destruction of the tumor, primarily thru ADCC.The monoclonals (mAbs) that we have developed against specific immunogenic tumor membrane proteins have been studied in detail. These tumor proteins, when first defined, were referred to as tumor associated antigens. With the ability of the mAbs to demonstrate therapeutic antitumor activity in those patients with relatively advanced malignancies, the term tumor specific was introduced. Monoclonals that we were able to develop from tumor specific proteins derived from colon and pancreas cancer were found capable of targeting those tumors to induce apoptosis. We were also able to define immunogenic membrane proteins from lung (squamous and adenoCa) as well as prostate neoplasms. Monoclonals developed from these tumor antigens are in the initial phases of investigation with regard to their specificity and antitumor activity.Mabs capable of targeting the malignancies noted above were produced following immunization of BALBc mice with the Tumor Specific Antigens. The hybridomas that were screened and found to express the antibodies of interest appeared for the most part as IgG2a's. It became apparent after a short period of time that stability of the Fab CDR loops as well as the therapeutic efficacy of the hybridoma mAbs could be lost. Stability was achieved by chimerization and or humanization. The resulting mAbs were found to switch their isotypes to an IgG1 subsequent to chimerization and or humanization, when expressed in CHO cells. The monoclonals, so produced, were not only more efficient in controlling tumor growth but minimized the development of a HAMA response.Because of 1) the specificity of this group of monoclonal antibodies in targeting well defined immunogenic proteins that were expressed on the tumor cell membrane,2) their lack of cross reactivity to normal tissue, 3) relatively low toxicity when delivered intravenously, 4) rapid targeting of tumor cell populations (4-6 hrs in vitro) and their 5) ability to destroy xenograft transplants (in vivo) within days of delivery, these mAbs were felt to be ideal for possible use in the treatment of patients with recurrent and or metastatic tumors.Initial clinical studies have been planned for following the filing of an IND. It is required by FDA that the potential effects of tumor control and toxicity be defined using the naked antibodies produced under GMP conditions, In those situations where patients with recurrent malignancies are to be studied we have come to realize that a number of factors can influence the response to monoclonal therapy. This includes the amount of shed antigen in the serum at the time of treatment that could initiate immune complex formation as well as the shedding of inhibitory material into the serum possibly effecting an immune response. As such we plan to eventually employ the therapeutic mAbs in combination with chemotherapy as a means of enhancing the immunogenicity of the tumor system being treated and to possibly weaken the malignant growth for easier destruction by the mAb. We will also look at the combination of mAbs with immunostimulants such as GMCSF and IL-2 (fusion proteins) and eventual conjugation of the mAbs with alpha and possibly B-emitters to help in targeting bystander cells. The present paper reviews the potential therapeutic value of such mAbs in the treatment of recurrent malignancies, especially those having failed chemotherapy in established clinical trials.
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PMID:The therapeutic value of monoclonal antibodies directed against immunogenic tumor glycoproteins. 2106 Jul 31

Preclinical and clinical trials demonstrated that use of oncolytic viruses (OVs) is a promising new therapeutic approach to treat multiple types of cancer. To further improve their viral oncolysis, experimental strategies are now combining OVs with different cytotoxic compounds. In this study, we investigated the capacity of triptolide - a natural anticancer molecule - to enhance vesicular stomatitis virus (VSV) oncolysis in OV-resistant cancer cells. Triptolide treatment increased VSV replication in the human prostate cancer cell line PC3 and in other VSV-resistant cells in a dose- and time-dependent manner in vitro and in vivo. Mechanistically, triptolide (TPL) inhibited the innate antiviral response by blocking type I interferon (IFN) signaling, downstream of IRF3 activation. Furthermore, triptolide-enhanced VSV-induced apoptosis in a dose-dependent fashion in VSV-resistant cells, as measured by annexin-V, cleaved caspase-3, and B-cell lymphoma 2 staining. In vivo, using the TSA mammary adenocarcinoma and PC3 mouse xenograft models, combination treatment with VSV and triptolide delayed tumor growth and prolonged survival of tumor-bearing animals by enhancing viral replication. Together, these results demonstrate that triptolide inhibition of IFN production sensitizes prostate cancer cells to VSV replication and virus-mediated apoptosis.
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PMID:Triptolide-mediated inhibition of interferon signaling enhances vesicular stomatitis virus-based oncolysis. 2398 99

Histone modifications play critical roles in the progression of non-small cell lung cancer (NSCLC), which accounts for almost 85% of all diagnosed lung cancers. Magnolol and polyphenol mixture (PM) derived from Magnolia officinalis exhibited remarkable antitumor activities in lung cancer. However, the epigenetic effects and molecular mechanisms of magnolol and PM in NSCLC have yet to be reported. In this study, the epigenetic effects of magnolol and PM in NSCLC were examined in vitro and in vivo. Results revealed that magnolol and PM significantly suppressed the expression levels and function of class I histone deacetylases (HDACs). In A549 and H1299 cells, magnolol and PM remarkably induced cell apoptosis by arresting the cell cycle in the G0/G1 phase while simultaneously activating various pro-apoptotic signals, including TRAIL-R2 (DR5), Bax, caspase 3, cleaved caspase 3, and cleaved PARP. However, these apoptosis-promoting effects could be attenuated by TSA, which is a specific class I HDACs inhibitor. ChIP assays also demonstrated that magnolol and PM significantly enriched the histone acetyl mark (H3K27ac) in the promoter region of DR5. In A549 xenograft model, magnolol and PM notably reduced tumor growth by 44.40% and 35.40%, respectively. Therefore, magnolol and PM, as potential inhibitors of class I HDACs, induced tumor cell apoptosis and suppressed tumor growth partially by epigenetically activating DR5, which is a key protein in death receptor signaling pathway.
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PMID:Novel histone deacetylase inhibitors derived from Magnolia officinalis significantly enhance TRAIL-induced apoptosis in non-small cell lung cancer. 2726 46